The research projects carried out under this program grant in the past have focused on the complex pathophysiology of diseases of the liver and porta circulation. In particular, the hemodynamic and metabolic changes seen during liver perfusion, liver preservation and transplantation and in portacaval shunting have been studied extensively. Associated and related projects include biochemical observations on urea synthesis and immunochemical studies on the hepatitis associated antigen. Other studies have led to an increasing interest in energy metabolism in liver disease; a new concept regarding the control of energy metabolism during semistarvation is developing which emphasizes the importance of gluconeogenesis, ureogenesis and ketogenesis and focuses on substrate control of these pathways. Continuation and projection of the program will involve the characterization and analysis of cellular and organ function in the liver as an extension of previous and continuing studies. New methods will be applied to the investigation of the complex cellular substrate - endocrine changes in hepatocellular disease. Specifically, the relationship of circulating peptides and small proteins to the pathophysiological changes of liver disease will be studied and efforts directed towards isolation and characterization of these substances by immunochemical techniques. A presumed intimate connection between the appearance of these substances and the failure of endotoxin inactivation by the liver is a related project. Focus on systemic efforts as manifested by renal and cerebral dysfunction brings these projects into close relationship. Auxillary transplantation in various species in the laboratory will be continued as will techniques of liver preservation. The rejection response to xenografting has obviously been a major obstacle but some encouraging progress has already been made. Clinical studies on patients undergoing portal-systemic shunting operations have involved pressure and flow studies which in a preliminary way, appear to serve as predictors of the various postshunt syndromes. These observations will be continued and related to the biochemical studies referred to above.